tbuckley/cabot-search huggingface dataset:
Using Circulating Tumor DNA in Colorectal Cancer: Current and Evolving Practices
Authors: Midhun Malla, Jonathan M Loree, Pashtoon Murtaza Kasi, Aparna Raj Parikh
Journal: Journal of Clinical Oncology (2022)

There exists a tremendous opportunity in identifying and determining the appropriate predictive and prognostic biomarker(s) for risk stratification of patients with colorectal cancers (CRCs). Circulating tumor DNA (ctDNA) has emerged as a promising prognostic and possibly predictive biomarker in the personalized management of patients with CRCs. The disease is particularly suited to a liquid biopsy-based approach since there is a great deal of shedding of circulating tumor fragments (cells, DNA, methylation markers, etc). ctDNA has been shown to have several potential applications, including detecting minimal residual disease (MRD), monitoring for early recurrence, molecular profiling, and therapeutic response prediction. The utility of ctDNA has broadened from its initial use in the advanced/metastatic setting for molecular profiling and detection of acquired resistance mechanisms, toward identifying MRD, as well as early detection. Prospective studies such as CIRCULATE, COBRA, Dynamic II/III, and ACT3 are underway in the MRD setting to further understand how ctDNA may be used to inform clinical decision making using both tumor-informed and tumor-agnostic platforms. These prospective studies use ctDNA to guide management of patients with CRC and will be critical to help guide how and where ctDNA should or should not be used in clinical decision making. It is also important to understand that there are different types of ctDNA liquid biopsy platforms, each with advantages and disadvantages in different clinical indications. This review provides an overview of the current and evolving use of ctDNA in CRC.
A computational solution for bolstering reliability of epigenetic clocks: implications for clinical trials and longitudinal tracking
Authors: Albert T. Higgins-Chen, Kyra L. Thrush, Yunzhang Wang, Christopher J. Minteer, Pei-Lun Kuo, Meng Wang, Peter Niimi, Gabriel Sturm, Jue Lin, Ann Zenobia Moore, Stefania Bandinelli, Christiaan H. Vinkers, Eric Vermetten, Bart P. F. Rutten, Elbert Geuze, Cynthia Okhuijsen-Pfeifer, Marte Z. van der Horst, Stefanie Schreiter, Stefan Gutwinski, Jurjen J. Luykx, Martin Picard, Luigi Ferrucci, Eileen M. Crimmins, Marco P. Boks, Sara Hägg, Tina T. Hu-Seliger, Morgan E. Levine
Journal: Nature Aging (2022)
Author Correction: Cytokine release syndrome-like serum responses after COVID-19 vaccination are frequent and clinically inapparent under cancer immunotherapy
Authors: Thomas Walle, Sunanjay Bajaj, Joscha A. Kraske, Thomas Rösner, Christiane S. Cussigh, Katharina A. Kälber, Lisa Jasmin Müller, Sophia Boyoung Strobel, Jana Burghaus, Stefan M. Kallenberger, Christoph K. Stein-Thöringer, Maximilian Jenzer, Antonia Schubert, Steffen Kahle, Anja Williams, Birgit Hoyler, Lin Zielske, Renate Skatula, Stefanie Sawall, Mathias F. Leber, Russell Z. Kunes, Johannes Krisam, Carlo Fremd, Andreas Schneeweiss, Jürgen Krauss, Leonidas Apostolidis, Anne Katrin Berger, Georg M. Haag, Stefanie Zschäbitz, Niels Halama, Christoph Springfeld, Romy Kirsten, Jessica C. Hassel, Dirk Jäger, Omar Abdelrahim, Elena Busch, Patrick Derigs, Katharina Dischinger, Fouad Mitri, Kerstin Schmidt, Irfan A. Bhatti, Barbara Grün, Nicolas Hohmann, Lena Woydack, Xin-Wen Zhang, Dyke Ferber, Andreas Mock, Tillmann Pompecki, Timo Schank, Carlo Fremd, Georg M. Haag, Niels Halama, Romy Kirsten, Jessica C. Hassel, Dirk Jäger, Guy Ungerechts
Journal: Nature Cancer (2022)

In the version of this article initially published, salient aspects of patient outcomes were not clearly articulated in the abstract, which has now been revised to include the text "Within 4 weeks after vaccination, serious adverse events occurred in eight patients (12.5% 95% CI 5.6-23%): six patients were hospitalized due to events common under cancer therapy including immune related adverse events and two patients died due to conditions present before vaccination".The changes have been made in the HTML and PDF versions of the article.
Patient-reported outcomes in ZUMA-7, a phase 3 study of axicabtagene ciloleucel in second-line large B-cell lymphoma
Authors: Mahmoud Elsawy, Julio C. Chavez, Irit Avivi, Jean-François Larouche, Luciano Wannesson, Kate Cwynarski, Keren Osman, Kelly Davison, Jakob D. Rudzki, Saurabh Dahiya, Kathleen Dorritie, Samantha Jaglowski, John Radford, Franck Morschhauser, David Cunningham, Alejandro Martin Garcia-Sancho, Dimitrios Tzachanis, Matthew L. Ulrickson, Reem Karmali, Natasha Kekre, Catherine Thieblemont, Gunilla Enblad, Peter Dreger, Ram Malladi, Namita Joshi, Wei-Jhih Wang, Caitlyn T. Solem, Julia Thornton Snider, Paul Cheng, Christina To, Marie José Kersten
Journal: Blood (2022)

Here, we report the first comparative analysis of patient-reported outcomes (PROs) with chimeric antigen receptor T-cell therapy vs standard-of-care (SOC) therapy in second-line relapsed/refractory large B-cell lymphoma (R/R LBCL) from the pivotal randomized phase 3 ZUMA-7 study of axicabtagene ciloleucel (axi-cel) vs SOC. PRO instruments were administered at baseline, day 50, day 100, day 150, month 9, and every 3 months from randomization until 24 months or an event-free survival event. The quality of life (QoL) analysis set comprised patients with a baseline and ≥1 follow-up PRO completion. Prespecified hypotheses for Quality of Life Questionnaire-Core 30 (QLQ-C30) physical functioning, global health status/QoL, and EQ-5D-5L visual analog scale (VAS) were tested using mixed-effects models with repeated measures. Clinically meaningful changes were defined as 10 points for QLQ-C30 and 7 for EQ-5D-5L VAS. Among 359 patients, 296 (165 axi-cel, 131 SOC) met inclusion criteria for QoL analysis. At day 100, statistically significant and clinically meaningful differences in mean change of scores from baseline were observed favoring axi-cel over SOC for QLQ-C30 global health status/QoL (estimated difference 18.1 [95% confidence interval (CI), 12.3-23.9]), physical functioning (13.1 [95% CI, 8.0-18.2]), and EQ-5D-5L VAS (13.7 [95% CI, 8.5-18.8]; P < .0001 for all). At day 150, scores significantly favored axi-cel vs SOC for global health status/QoL (9.8 [95% CI, 2.6-17.0]; P = .0124) and EQ-5D-5L VAS (11.3 [95% CI, 5.4-17.1]; P = .0004). Axi-cel showed clinically meaningful improvements in QoL over SOC. Superior clinical outcomes and favorable patient experience with axi-cel should help inform treatment choices in second-line R/R LBCL. This trial was registered at www.clinicaltrials.gov as #NCT03391466.
Ly6C <sup>hi</sup> monocytes balance regulatory and cytotoxic CD4 T cell responses to control virus-induced immunopathology
Authors: Céline Maquet, Jérôme Baiwir, Pauline Loos, Lucia Rodriguez-Rodriguez, Justine Javaux, Rémy Sandor, Fabienne Perin, Padraic G. Fallon, Matthias Mack, Didier Cataldo, Laurent Gillet, Bénédicte Machiels
Journal: Science Immunology (2022)

Gammaherpesviruses (γHVs) have coevolved with their host, leading to a remarkably high infection prevalence and establishment of latency. The lifelong persistence of γHVs in hosts appears to broadly shape host immunity, and we show here that pulmonary infection with Murid herpesvirus 4 (MuHV-4), a mouse γHV, drives the recruitment of Ly6C hi monocytes (MOs) into the airway, thereby modulating the host immune response. The absence of Ly6C hi MOs is associated with severe virus-induced immunopathology and the systemic release of inflammatory mediators. Mechanistically, MuHV-4–imprinted MOs recruit CD4 T cells to the airways and trigger immunosuppressive signaling pathways through the PD-L1/PD-1 axis, thereby dampening the deleterious activation of cytotoxic CD4 T cells. These results uncover a role for Ly6C hi MOs in modulating CD4 T cell functions and reveal pathways that could be targeted therapeutically to reduce detrimental immunopathological responses associated with respiratory viral infections.
Patients cannot consent to care unless they know how much it costs
Authors: Leah Pierson, Emma Pierson
Journal: BMJ (2022)

Americans rarely know how much their medical care will cost and most have received a medical bill that they did not expect. 1 The lack of transparency around medical costs leads people to avoid seeking necessary care, fosters distrust in the US healthcare system, and has implications for informed consent. 2 If patients do not know how much their care will cost-and the financial risk they may face as a result-can they really consent to it?
Association of Access to Crisis Intervention Teams With County Sociodemographic Characteristics and State Medicaid Policies and Its Implications for a New Mental Health Crisis Lifeline
Authors: Helen Newton, Tamara Beetham, Susan H. Busch
Journal: JAMA Network Open (2022)

<h3>Importance</h3> The mental health crisis lifeline 988 will begin operating July 16, 2022. In the absence of appropriately trained first responders, including crisis intervention teams (CITs), persons experiencing behavioral health crises face the risk of incarceration and even death. <h3>Objective</h3> To assess county-level access to CIT in 2015 and 2020 and its association with area characteristics and state policies in 2020. <h3>Design, Setting, and Participants</h3> This cross-sectional study included 10 430 facilities from the 2015 National Directory of Mental Health Treatment Facilities and 10 591 facilities from the 2020 National Directory of Mental Health Treatment Facilities, attributed to 3142 US counties. <h3>Exposures</h3> Area measures included need (suicide, drug-related overdose mortality), rurality, and demographic characteristics. State-level policies included 5 Medicaid policies enacted prior to 2020 and 2 recent policies intended to assist implementation of the 988 lifeline. <h3>Main Outcomes and Measures</h3> Whether there was at least 1 facility that reported offering a CIT that handled acute mental health issues at the facility or off-site for each county in 2015 and, separately, in 2020. <h3>Results</h3> Most US residents (88%) resided in a county with at least 1 facility offering CIT, although half of US counties had no facility offering CIT (2015: 1537 of 3142 [49%]; 2020: 1512 [48%]). Almost 1 in 5 counties, representing 9% of the population, experienced a change in county-level access from 2015 to 2020. Unadjusted analyses indicated residents of counties without vs with CIT access were more likely to be older and uninsured (top quartile of percentage of residents aged &gt;55 years: 502 of 1512 [33%] vs 283 of 1630 [17%];<i>P</i> &lt; .001; top quartile of percentage of residents uninsured: 500 [33%] vs 285 [17%];<i>P</i> &lt; .001) and were more likely be rural (frontier: 500 [33%] vs 144 [9%];<i>P</i> &lt; .001). Similar results, excluding counties in the top quartile of residents aged older than 55 years, were found in adjusted analyses. Counties without vs with CIT access were less likely to be in states that expanded Medicaid (788 [52%] vs 1102 [68%];<i>P</i> = .01) and in states that allow Medicaid to pay for short-term stays in psychiatric hospitals (34 [2%] vs 73 [4%];<i>P</i> = .02). Other Medicaid-related associations were not statistically significant in adjusted analyses. <h3>Conclusions and Relevance</h3> In this study, most US residents lived in counties with access to at least 1 CIT, but fewer than half of US counties had such access. Policies to encourage facilities in rural counties to offer CIT may help realize the potential of the new lifeline.
On the Importance of Considering Glycosylation When Evaluating Biologic Therapies
Authors: Mathieu Lemaire
Journal: Journal of the American Society of Nephrology (2022)

Ravaniand colleagues must be commended for successfully publishing an important randomized controlled trial addressing the role of two anti-CD20 mAbs, rituximab and ofatumumab, for pediatric nephrotic syndrome.1 Rituximab is a chimeric mouse/human mAb, whereas ofatumumab is an entirely human mAb. The authors mention that one major limitation of rituximab-based therapy is that many patients develop antirituximab antibodies, which dramatically reduces efficacy. Further, they posit that ofatumumab may be superior to rituximab because it has a higher affinity for the human CD20 epitope and triggers a more vigorous complement response.1 It would have been necessary to highlight that rituximab is very likely to have a significantly less immunogenic glycosylation profile than ofatumumab. This phenomenon relates to the properties of specific neuraminic acids (also known as sialic acids) that decorate the tip of most glycans.2 There are two major types of neuraminic acids in the animal kingdom: N-acetylneuraminic acid (Neu5Ac) and N-glycolylneuraminic acid (Neu5Gc). These monosaccharides must be activated via linkage to cytidine monophosphate (CMP) to be added to the termini of glycans by sialyltransferases. Interestingly, cells produce Neu5Gc when the enzyme cytidine monophosphate N-acetylneuraminic acid hydroxylase (CMAH) adds an oxygen atom to CMP-Neu5Ac.2 Due to a deletion in the gene encoding for CMAH, all humans cannot synthesize CMP-Neu5Gc. As a result, most humans have preexisting anti-Neu5Gc antibodies that likely developed after exposure to animal-derived proteins (xeno-antigens).2 This means that intravenous infusion of recombinant antibodies produced in animal cells may significantly reduce the half-life in many patients because of the robust immune response triggered after exposure.3 This phenomenon would be predicted to worsen with additional infusions. Both rituximab and ofatumumab are N-glycosylated in the Golgi of the animal cell lines used to produce them—the CHO (Chinese hamster ovary) and NS0 (murine myeloma) cells, respectively. CHO cells are unusual because they express lower Cmah levels than other commonly used animal cell lines, such as NS0 cells.4 As a result, the proportion of N-linked glycans capped with Neu5Ac is much lower in recombinant proteins produced in CHO cells. On the basis of the above discussion, it would have been essential to share data about the patients who experienced relapses during the trial and were prescribed additional infusions of rituximab or ofatumumab. It would also have been ideal to monitor the titers of antirituximab and anti-Neu5Gc antibodies in both arms of the study. Patients with low preexisting anti-Neu5Gc levels would be predicted to fare better. Disclosures The author has nothing to disclose. Funding None.
The Mechanisms of Action of Tumor Treating Fields
Authors: Justin C. Moser, Ellaine Salvador, Karina Deniz, Kenneth Swanson, Jack Tuszynski, Kristen W. Carlson, Narasimha Kumar Karanam, Chirag B. Patel, Michael Story, Emil Lou, Carsten Hagemann
Journal: Cancer Research (2022)

Abstract Tumor treating fields (TTFields), a new modality of cancer treatment, are electric fields transmitted transdermally to tumors. The FDA has approved TTFields for the treatment of glioblastoma multiforme and mesothelioma, and they are currently under study in many other cancer types. While antimitotic effects were the first recognized biological anticancer activity of TTFields, data have shown that tumor treating fields achieve their anticancer effects through multiple mechanisms of action. TTFields therefore have the ability to be useful for many cancer types in combination with many different treatment modalities. Here, we review the current understanding of TTFields and their mechanisms of action.
Clonal hematopoiesis is not significantly associated with COVID-19 disease severity
Authors: Yifan Zhou, Ruba Shalhoub, Stephanie N. Rogers, Shiqin Yu, Muxin Gu, Margarete A. Fabre, Pedro M. Quiros, Tae-Hoon Shin, Arch Diangson, Wenhan Deng, Shubha Anand, Wenhua Lu, Matthew Cullen, Anna L. Godfrey, Jacobus Preller, Jerome Hadjadj, Emmanuelle Jouanguy, Aurélie Cobat, Laurent Abel, Frederic Rieux-Laucat, Benjamin Terrier, Alain Fischer, Lara Novik, Ingelise J. Gordon, Larisa Strom, Martin R. Gaudinski, Andrea Lisco, Irini Sereti, Thomas J. Gniadek, Andrea Biondi, Paolo Bonfanti, Luisa Imberti, Clifton L. Dalgard, Yu Zhang, Kerry Dobbs, Helen C. Su, Luigi D. Notarangelo, Colin O. Wu, Peter J.M. Openshaw, Malcolm G. Semple, Ziad Mallat, Kenneth Baillie, Cynthia E. Dunbar, George S. Vassiliou
Journal: Blood (2022)
Reactogenicity and Concomitant Administration of the COVID-19 Booster and Influenza Vaccine
Authors: Kathryn T. Hall, Valerie E. Stone, Bisola Ojikutu
Journal: JAMA Network Open (2022)

Anne M. Hause, PhD, MSPH; Bicheng Zhang, MS; Xin Yue, MS; Paige Marquez, MSPH; Tanya R. Myers, PhD, MSci; Casey Parker, BSN; Julianne Gee, MPH; John Su, MD, PhD, MPH; Tom T. Shimabukuro, MD, MPH, MBA; David K. Shay, MD, MPH
Local delivery of low-dose anti–CTLA-4 to the melanoma lymphatic basin leads to systemic T <sub>reg</sub> reduction and effector T cell activation
Authors: Kim M. van Pul, Jessica C. L. Notohardjo, Marieke F. Fransen, Bas D. Koster, Anita G. M. Stam, Dafni Chondronasiou, Sinéad M. Lougheed, Joyce Bakker, Vinitha Kandiah, M. Petrousjka van den Tol, Karin Jooss, Ronald J. C. L. M. Vuylsteke, Alfons J. M. van den Eertwegh, Tanja D. de Gruijl
Journal: Science Immunology (2022)

Preclinical studies show that locoregional CTLA-4 blockade is equally effective in inducing tumor eradication as systemic delivery, without the added risk of immune-related side effects. This efficacy is related to access of the CTLA-4 blocking antibodies to tumor-draining lymph nodes (TDLNs). Local delivery of anti-CTLA-4 after surgical removal of primary melanoma, before sentinel lymph node biopsy (SLNB), provides a unique setting to clinically assess the role of TDLN in the biological efficacy of locoregional CTLA-4 blockade. Here, we have evaluated the safety, tolerability, and immunomodulatory effects in the SLN and peripheral blood of a single dose of tremelimumab [a fully human immunoglobulin gamma-2 (IgG2) mAb directed against CTLA-4] in a dose range of 2 to 20 mg, injected intradermally at the tumor excision site 1 week before SLNB in 13 patients with early-stage melanoma (phase 1 trial; NCT04274816). Intradermal delivery was safe and well tolerated and induced activation of migratory dendritic cell (DC) subsets in the SLN. It also induced profound and durable decreases in regulatory T cell (Treg) frequencies and activation of effector T cells in both SLN and peripheral blood. Moreover, systemic T cell responses against NY-ESO-1 or MART-1 were primed or boosted (N = 7), in association with T cell activation and central memory T cell differentiation. These findings indicate that local administration of anti-CTLA-4 may offer a safe and promising adjuvant treatment strategy for patients with early-stage melanoma. Moreover, our data demonstrate a central role for TDLN in the biological efficacy of CTLA-4 blockade and support TDLN-targeted delivery methods.
Insomnia: Large study shows how well different drugs work
Authors: Jacqui Wise
Journal: BMJ (2022)

<b>Objective</b> To determine whether familial risk of cancer is limited to early onset cases. <b>Design</b> Nationwide prospective cohort study. <b>Setting </b>Nationwide Swedish Family-Cancer Database. <b>Participants</b> All Swedes born after 1931 and their biological parents, totalling &gt;12.2 million individuals, including &gt;1.1 million cases of first primary cancer. <b>Main outcome measures</b> Familial risks of the concordant cancers by age at diagnosis. <b>Results</b> The highest familial risk was seen for offspring whose parents were diagnosed at an early age. Familial risks were significantly increased for colorectal, lung, breast, prostate, and urinary bladder cancer and melanoma, skin squamous cell carcinoma, and non-Hodgkin’s lymphoma, even when parents were diagnosed at age 70-79 or 80-89. When parents were diagnosed at more advanced ages (≥90), the risk of concordant cancer in offspring was still significantly increased for skin squamous cell carcinoma (hazard ratio 1.9, 95% confidence interval 1.4 to 2.7), colorectal (1.6, 1.2 to 2.0), breast (1.3, 1.0 to 1.6), and prostate cancer (1.3, 1.1 to 1.6). For offspring with a cancer diagnosed at ages 60-76 whose parents were affected at age &lt;50, familial risks were not significantly increased for nearly all cancers. <b>Conclusion</b> Though the highest familial risks of cancer are seen in offspring whose parents received a diagnosis of a concordant cancer at earlier ages, increased risks exist even in cancers of advanced ages. Familial cancers might not be early onset in people whose family members were affected at older ages and so familial cancers might have distinct early and late onset components.
Incidence and Relative Risk of COVID-19 in Adolescents and Youth Compared With Older Adults in 19 US States, Fall 2020
Authors: Moshe Schneiderman, Barbara Rumain, Leon Kaganovskiy, Allan Geliebter
Journal: JAMA Network Open (2022)

Adolescents have been thought to be low in susceptibility to COVID-19 compared with older adults. Data regarding incidence and risk of COVID-19 are needed to convey risk of infection and inform prevention messaging, especially because US states such as Florida are recommending against vaccinating individuals ages 5 to 17 years and because more infections among adolescents could signal potentially higher incidence of long COVID.To compare incidence rates and relative risk of infection among US adolescents and youth with those of older adults for wild-type SARS-CoV-2.This cross-sectional study included persons living in 19 US states that experienced surges from the start of the pandemic through fall 2020. Participants were all individuals reported as cases on state health department websites for the age groups and states studied. Age groups included adolescents (ages 10 to 19 years), youth (ages 15 to 24 years or 18 to 24 years), adolescents and youth combined (ages 10 to 24 years), and older adults (either age 60 years or 65 years and older), with age thresholds dependent on individual state data. Data were analyzed between June 2021 and January 2022.Incidence rates for the wild-type SARS-CoV-2 strain; the relative risk of infection in adolescents and youth compared with older adults, based on the incidence rate ratio (IRR).In 16 of 19 states, the IRR of COVID-19 infection in adolescents and youth was significantly greater than in older adults. For example, in Florida, the incidence rate in adolescents and youth was 0.055 compared with 0.028 in older adults-adolescents and youth had 1.94 times the risk of contracting COVID-19 compared with older adults (IRR, 1.94; 95% CI, 1.92-1.95).Results from this cross-sectional study with US data were contrary to studies from Asia and Europe indicating lower susceptibility of adolescents than older adults. Our findings with the wild-type strain were consistent with findings reported in the UK for the Delta variant and underscored that even with the wild-type lineage, incidence among adolescents and youth exceeded that in older adults.
Overdose Prevention Centers: An Essential Strategy to Address the Overdose Crisis
Authors: Elizabeth A. Samuels, Dennis A. Bailer, Annajane Yolken
Journal: JAMA Network Open (2022)

Alex Harocopos, PhD, MSc; Brent E. Gibson, PhD; Nilova Saha, LCSW; Michael T. McRae, PhD; Kailin See; Sam Rivera; Dave A. Chokshi, MD, MSc
The terrible waste caused by our outdated system of care records
Authors: Richard Smith
Journal: BMJ (2022)

The terrible waste caused by our outdated system of care records Richard Smith chairEver since I thought about it for the first time, some 15 years ago, it's been obvious to me that a person's health and care records should belong to that person not to anybody else.That's why I agreed to be the chair of Patients Know Best, a company that brings together all the health and social care records of patients and puts them under the control of the patient.